Unknown

Dataset Information

0

SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication.


ABSTRACT: The SPRTN metalloprotease is essential for DNA-protein crosslink (DPC) repair and DNA replication in vertebrate cells. Cells deficient in SPRTN protease exhibit DPC-induced replication stress and genome instability, manifesting as premature ageing and liver cancer. Here, we provide a body of evidence suggesting that SPRTN activates the ATR-CHK1 phosphorylation signalling cascade during physiological DNA replication by proteolysis-dependent eviction of CHK1 from replicative chromatin. During this process, SPRTN proteolyses the C-terminal/inhibitory part of CHK1, liberating N-terminal CHK1 kinase active fragments. Simultaneously, CHK1 full length and its N-terminal fragments phosphorylate SPRTN at the C-terminal regulatory domain, which stimulates SPRTN recruitment to chromatin to promote unperturbed DNA replication fork progression and DPC repair. Our data suggest that a SPRTN-CHK1 cross-activation loop plays a part in DNA replication and protection from DNA replication stress. Finally, our results with purified components of this pathway further support the proposed model of a SPRTN-CHK1 cross-activation loop.

SUBMITTER: Halder S 

PROVIDER: S-EPMC6637133 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

altmetric image

Publications


The SPRTN metalloprotease is essential for DNA-protein crosslink (DPC) repair and DNA replication in vertebrate cells. Cells deficient in SPRTN protease exhibit DPC-induced replication stress and genome instability, manifesting as premature ageing and liver cancer. Here, we provide a body of evidence suggesting that SPRTN activates the ATR-CHK1 phosphorylation signalling cascade during physiological DNA replication by proteolysis-dependent eviction of CHK1 from replicative chromatin. During this  ...[more]

Similar Datasets

2019-11-08 | PXD006741 | Pride
| S-EPMC7116149 | biostudies-literature
| S-EPMC7534798 | biostudies-literature
| S-EPMC4424366 | biostudies-literature
| S-EPMC5128727 | biostudies-literature
| S-EPMC7870818 | biostudies-literature
| S-EPMC2957206 | biostudies-literature
| S-EPMC2708895 | biostudies-literature
| S-EPMC4517752 | biostudies-literature
| S-EPMC3358916 | biostudies-literature